Polymeric IgA and IgM (polymeric immunoglobulins, pIg) bind to a receptor on the basolateral surface of many types of epithelial cells, and are endocytosed, transported across the cell in vesicles, and exocytosed into external secretions. During transport, a portion of the receptor is cleaved off and released into the secretion with the pIg. This released fragment is called secretory component (SC). The goal of this research is to determine the molecula mechanism of transcellular transport of the pIg and the pIg receptor (pIgR). This is important for 3 reasons. First, transport of pIg into secretions is a major defense against infection. Second, failure to transport IgA may lead to IgA immune complex deposition, which occurs in Berger's disease, Henoch-Schonlein Purpurae, and possibly liver disease. Third, pIgR is an excellent model for studying general mechanisms of protein sorting and traffic, and can thus provide insights relevant to a broad range of biomedical problems. During the period of this proposal, several approaches will be used to study the mechanism of pIgR transport. First, it is known that inhibitors of acidification of endocytotic vesicles disrupt the transport of other endocytosed receptors and the effects of such inhibitors on pIgR transport will be investigated. Second, proteins that bind to the pIgR and may mediate its transport will be isolated and characterized. Third, the introns and exons in the pIgR gene will be located in order to help understand the structural and functional units of the pIgR molecule. Fourth, the pIgR gene will be introduced and expressed in mammalian cells. By altering the gene in vitro by deletions, mutagenesis, and recombination, the portion(s) of the pIgR molecule needed for transport can be determined.